Human infections with Asian and European hantaviruses can result in hemorrhagic fever

Measles virus (MV) infection and vaccination induce long-lasting immunity and neutralizing-antibody responses that are directed against the MV haemagglutinin (H) and the fusion (F) protein. A new MV genotype, D7, emerged recently in western Germany and rapidly replaced the long-term endemically circulating genotypes C2 and D6. Analysis of the H gene of C2, D6, D7 and vaccine viruses revealed uniform sequences for each genotype. Interestingly, a consistent exchange of seven distinct amino acids in the D7 H was observed when compared with residues shared between C2, D6 and vaccine viruses, and one exchange (D416RN) in the D7 H was associated with an additional N-linked glycosylation. In contrast, the F gene is highly conserved between MVs of these genotypes. To test whether the D7 H protein escapes from antibody responses that were raised against earlier circulating or vaccine viruses, the neutralizing capacity of mAbs recognizing seven distinct domains on the H of an Edmonston-related MV was compared. The mAbs revealed a selective and complete loss of two neutralizing epitopes on the D7 H when compared with C2, D6 and vaccine viruses. To assess whether these alterations of the D7 H affect the neutralizing capacity of polyclonal B-cell responses, genotype-specific antisera were produced in cotton rats. However, no significant genotype-dependent difference was found. Likewise, human sera obtained from vaccinees (n=7) and convalescents (n=6) did not distinguish between the MV genotypes. Although the hypothesis of selection of D7 viruses by pre-existing neutralizing antibodies is compatible with the differing pattern of neutralizing epitopes on the H protein, it was not confirmed by the results of MV neutralization with polyclonal sera. INTRODUCTIONMeasles virus (MV) infection and vaccination with a liveattenuated vaccine induce long-lasting immunity. Protection against measles is mediated both by antibodies and by T-cell immunity. Neutralizing-antibody responses are directed solely against the viral surface glycoproteins, the haemagglutinin (H) and the fusion (F) protein. The H protein is responsible for attachment of the virion to host-cell receptors (Dörig et al., 1993;Naniche et al., 1993;Wild & Buckland, 1995;Tatsuo et al., 2000; Erlenhöfer et al., 2001;Schneider-Schaulies et al., 2001) and acts in concert with the F protein during fusion and virus entry (Wild et al., 1991). Neutralizing antibodies inhibit virus infection by preventing the interaction of the H protein with its cell receptors and by blocking fusion activity (Bouche et al., 2002).Wild-type MVs are currently divided into 22 genotypes, based on sequences derived from the N and H genes (WHO, 2003 et al., 2002). At asparagine residue 416, the D7 H has an additional potential site for N-linked glycosylation that seems to be restricted to viruses of more contemporary circulating genotypes (Rota et al., 1992;Saito et al., 1995;Kubo et al., 2003). As the H protein is the prime target for neutralizing and protective antibodies (Giraudon & Wild, 1985;Var...

The linear haemagglutinin noose epitope (HNE; aa 379-410) is a protective B-cell epitope and considered to be highly conserved in both the vaccine and the wild-type measles virus (MeV) haemagglutinin (H) proteins. Vaccine virus-derived monoclonal antibodies (mAbs) BH6 and BH216, which target the HNE, neutralized MeVs of genotypes B3, C2, D4, D5, D6, D7 and D8, and the vaccine strain Edmonston Zagreb. In the case of genotype H1, only strain Berlin.DEU/ 44.01 was neutralized by these mAbs, whereas strains Shenyang.CHN/22.99 and Sofia.BGR/ 19.05 were not. The H gene sequences of these two strains showed an exchange of proline 397 (P397) to leucine (L397). Mutated H proteins, with P397 exchanged to L and vice versa, were compared with original H proteins by indirect fluorescence assay. H proteins exhibiting P397 but not those with L397 were recognized by BH6 and BH216. This indicates that L397 leads to the loss of the neutralizing HNE. In contrast, human sera obtained from vaccinees (n510) did not discriminate between genotype H1 variants P397 and L397. This concurs with the epidemiological observation that the live-attenuated vaccine protects against both H1 variants. Furthermore, we demonstrated that MeVs of genotype H1 also lack the neutralizing epitopes defined by the vaccine virus-induced mAbs BH15, BH125 and BH47. The loss of several neutralizing epitopes, as shown for H1 viruses currently circulating endemically in Asia, implies that epitope monitoring should be considered to be included in measles surveillance.

In Lithuania at least two hantaviruses, DOBV and PUUV, circulate and cause human infections. Additional investigations are needed to study the seroprevalence more precisely and to search for clinical cases of hantavirus infections.